Chenodeoxycholic acid has exhibited valuable therapeutic activity, particularly as an agent for dissolution of cholesterol gallstones. This compound is currently obtained from cholic acid. An exemplary synthesis starting from cholic acid is described in U.S. Pat. No. 3,836,550. However, this process is of limited importance due to the circumstances which exist regarding the natural sources of cholic acid which is extracted from cow bile or with some additional processing from chicken bile. Calculations based on estimated demand for chenodeoxycholic acid assuming only one-third the potential patients utilize this drug indicate that such natural sources even if utilized to maximum potential could provide only a minor portion of such demand. Thus, an efficient synthesis from highly abundant starting materials is an important factor in determining whether chenodeoxycholic acid achieves its potential role in medicine.
Hydroxylation at the 7-position of compounds in the androstane and pregnane series is well known in the art. An early report by Kramli and Horvath, Nature, 4120, 619 (1948) indicated the 7-hydroxylation of cholesterol by incubation with Proactinomyces roseus was carried out but the actual configuration of the product was not determined. Well documented reports of 7-alpha-hydroxylation on the following substrates appear in the art:
deoxycorticosterone--Meystre et al., Helv. Chim. Acta 38, 381(1955). PA1 progesterone and related compounds--U.S. Pat. No. 2,753,290, U.S. Pat. No. 2,836,608, McAleer et al., J. Org. Chem. 23, 958 (1958). PA1 testosterones--U.S. Pat. No. 2,801,251, U.S. Pat. No. 2,960,436, Irmscher et al., Chemische Berichten 97, 3363 (1964). PA1 A-nor steroids--U.S. Pat. No. 3,005,018 Laskin and Weisenborn, Bact. Proc. 26, A26 (1962). PA1 17-alkyl androstanes and pregnenes--Singh et al., Can. J. of Microbiol. 13, 1271 (1967). PA1 androstenedione--Abdul-Hajj. Lloydia 33(2), 278 (1970). PA1 estradiols--Chem. Abstracts 86, 73006s (1977).
Botryodiplodia theobromae is known to be capable of 11-alpha-hydroxylating steroids (U.S. Pat. No. 3,047,470). Lasiodiplodia theobromae and Botryodiplodia theobromae are effective agents for the reduction of pyridine and of pyrimidine compounds. See for example Howe and Moore, J. Med. Chem. 14 (4), 287 (1971); British Pat. No. 1,183,850; and Howe et al., J. Med. Chem. 15, 1040 (1972). Lasiodiplodia theobromae has also been reported to oxidize mycophenolic acid. Jones et al., J. Chem. Soc. (C), 1725 (1970).